Homeostatic B Cell-Attracting chemokine 1 (BCA-1), otherwise known as CXCL13 (or ANGIE, BLC, BLR1L, ANGIE2, or Scyb13), is constitutively expressed in secondary lymphoid organs (e.g., spleen, lymph nodes, and Peyer's patches) by follicular dendritic cells (FDCs) and macrophages. See Gunn et al., Nature 391:799-803 (1998) and Carlsen et al., Blood 104(10):3021-3027 (2004). CXCL13 primarily acts through G-protein-coupled CXCR5 receptor (Burkitt's lymphoma receptor 1). CXCR5 is expressed, e.g., on mature B lymphocytes, CD4+ follicular helper T cells (Thf cells), a minor subset of CD8+ T cells, and activated tonsillar Treg cells. See Legler et al., J. Exp. Med. 187:655-660 (1998); Förster et al., Blood 84:830-840 (1994); Fazilleau et al., Immunity 30:324-335 (2009); Ansel et al., J. Exp. Med. 190:1123-1134 (1999); Lim et al., J. Clin. Invest. 114(11):1640-1649 (2004); and R. Förster, Chapter in Academic Press Cytokine Reference, August 2000.
Generation of B-cells having the potential for autoantibody (antibody against self-antigen) production is common under normal physiological conditions. However, such natural autoantibodies are low affinity IgM antibodies that exhibit wide-spectrum reactivity and strong a preference for soluble self antigens over cell surface antigens (see, e.g., Dichiero et al., J. Immunol. 134(2):765-771 (1985); Cote et al., Proc. Natl. Acad. Sci. 83:2959-2963 (1986)). Autoreactive low-affininty B-cells undergo apoptosis and, therefore, are unlikely to present a danger to a healthy organism.
In the absence of infection and during a normal immune response, CXCL13 and its receptor CXCR5 are involved in the homing of B-cells and follicular B-helper T cells into primary follicles in lymph nodes and spleen; germinal center formation; and lymphoid organogenesis. See, e.g., Förster et al., Cell 87:1037-1047 (1996).
CXCL13 and CXCR5-deficient mice demonstrated impaired development of Peyer patches and lymph nodes due to the lack of organized follicles. See Ansel et al., Nature 406:309-314 (2000). Furthermore, immunization with T-cell-dependent antigen in the context of the CXCL13 knockout phenotype led to the formation of misplaced and abnormally small germinal centres in the lymph nodes and spleens (Ansel et al.).
In a chronically-inflamed environment, ectopic germinal centres form within affected (often non-lymphoid) tissues. CXCL13 over-expression in these germinal centres by follicular dendritic cells (FDCs), accompanied by disregulation in interactions among FDCs, B-cells and follicular Th cells, reduced elimination of autoreactive B-cells and subsequent, antigen-driven, generation of affinity-mature long-lived plasma cells and memory B-cells producing high affinity IgG autoantibodies, which can result in the development of autoimmune and inflammatory disorders. See, e.g., Vinuesa et al., Immunology 9:845-857 (2009). Furthermore, over-expression of CXCR5 receptor in certain cancers has been reported to promote CXCL13-dependent cell proliferation and metastasis.
High-level expression of CXCL13 (BCA-1) and its receptor, CXCR5, has been observed in H. pylori-induced gastric lymphoid follicles and mucosa-associated lymphoid tissue (MALT) lymphomas. See, e.g., Mazzucchelli et al., J Clin Invest 104:R49-R54 (1999). Furthermore, CXCL13 (BCA-1) expression was found in all samples of H. pylori-induced gastritis. Id. In the gastric mucosa of H. heilmannii-infected wild-type mice, the mRNA expression level of CXCL13, which is known to be involved in organogenesis of lymphatic tissues (including MALT), was significantly higher than that of uninfected mice. See Nobutani et al., FEMS Immunol Med Microbiol 60:156-164 (2010).
The need for therapies that target CXCL13-mediated signaling pathways has become increasingly apparent in the recent years. The mechanisms of action for such treatments would include, e.g., blockade of CXCL13 interaction with its receptor resulting in interference with B cell and follicular B-helper T cell migration into inflamed tissues and germinal center formation (e.g., in the case of autoimmune disease) and inhibition of cancer cell proliferation and ability to spread in oncological disorders.